Thrombospondin (also known as thrombin sensitive protein or TSP) is a large molecular weight 180 kD glycoprotein composed of three identical disulfide-linked polypeptide chains. Thrombospondin has been purified by a number or procedures including exclusion chromatography (Lawler et al., J. Biol. Chem. (1978) 253:8609-16), heparin affinity chromatography (Lawler et al., Thromb. Res. (1981) 22:267-269), fibrinogen affinity chromatography (Tuszynski et al., J. Biol. Chem. (1985) 260:12240-5), barium chloride precipitation (Alexander et al., Biol. J. (1984) 217:67-71) and anion exchange chromatography with HPLC (Clezarolin et al., J. Chromatog. (1984) 296:249-56).
The complete amino acid sequence of TSP has been deduced from DNA clones prepared by various groups including Lawler et al., J. Cell Biol. (1986) 103:1635-48; Kobayashi et al., Biochemistry (1986) 25:8418-25; Dixit et al., Proc. Ntl. Acad. Sci. (1986) 83:5449-53; and Hennessy et al., J. Cell Biol. (1989) 108:729-36.
Kobayashi et al. (supra), Robson et al. (Nature (1988) 335:79-82) and Goundis et al. (Nature (1988) 335:82-85) compared the sequences of thrombospondin, thrombospondin-related anonymous protein, properdin, the terminal complement components, and circumsporozoite proteins and recognized a significant homology based around the consensus sequence (SEQ ID No. 1) W-S-P-C-S-V-T-C-G. While the sequence homology was recognized, there was no known use for such sequence.
The native thrombospondin molecule has been shown to potentiate tumor cell metastasis (Tuszynski et al., Cancer Research (1987) 47:4130-4133). The mechanisms by which the thrombospondin potentiation occurs are not presently well understood.
Thrombospondin and/or TSP-like proteins have been reported to have effects in the inhibition of angiogenesis (Rastinejad et al., Cell (1989) 56:345-355, and Good et al., J. Cell Biol. Suppl. (1989) 13B:30). The mechanism by which thrombospondin modulates angiogenesis is not well understood.
The present invention provides thrombospondin fragments and analogs which mimic or inhibit the biological activity of intact thrombospondin which find use in a variety of biological, prophylactic or therapeutic areas.